PROJECT SUMMARY/ABSTRACT NEUROPATHOLOGY CORE The Neuropathology (NP) Core provides for diagnostic neuropathological evaluations on patients and control subjects enrolled in the clinical core and on other well-clinically documented patients with neurodegenerative disease. The Core aims to gain enhanced understanding of the pathogenesis of AD, develop better biomarkers and discovery novel effective, therapeutic approaches. The protocols used by the NP core will be state of the art and consistent with 21st century brain banking procedures, which is essential to meet the increasingly sophisticated needs of the AD research community. Emphasis will be placed on delineating the presence of overlapping neurodegenerative syndromes such as vascular dementia, Lewy Body Disease, frontotemporal degeneration and prion disease, in addition to AD related pathology. In the current period of funding we performed over 130 autopsies, published over 65 peer reviewed manuscripts and provided tissue to over 50 investigators. In this renewal we will place emphasis on the center theme of this ADCC, which is elucidating the clinic-pathological substrates that underlie the transitions from normal aging to preclinical AD, preclinical AD to MCI, and MCI to the earliest stages of dementia. The overall objectives of the NP core of the NYU ADCC are to provide staff, technical resources, laboratory facilities and expertise for the investigation of structural and molecular properties of the brains of patients with AD and related dementia, as well as of normal controls. The aims of the NP core are: Aim 1: To perform rapid autopsies and obtain brains from ADC participants, using a standardized, state of the art protocol. Aim 2: Performed standardized state of the art neuropathological analysis and diagnosis of cases from the ADCC clinical core and affiliated cases, with a careful analysis of concomitant pathology. Aim 3: To maintain a state of the art brain tissue repository of unfixed frozen and fixed tissue from Aim 4: To conduct morphometric studies to establish better clinical neuropathological correlations for transitions of normal aging to preclinical AD, preclinical AD to MCI and MCI to early dementia. Aim 5: To foster training of investigators and residents on the utilization of neuropathological techniques, train neuropathologists and enhancing the use of Core tissue/resources for the identification of novel biomarkers and therapeutic approaches for neurodegenerative diseases.